Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-29
2002-08-20
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C514S925000
Reexamination Certificate
active
06436975
ABSTRACT:
The Present invention relates to compositions to be used in the therapy and in the prevention of the ulcer relapses and, in general of the dyspepsias. More particularly it relates to compositions having an improved gastroprotectiie activity combined with an high acid secretion inhibition activity.
The products known in the art and those commercialized and used in the ulcer therapy are compounds which perform an anti-secretory activity (acid secretion inhibition). See for instance “New Guide to Medicine & Drugs” Brit. Medical Assoc. Editor, 1997, pages 108-109. Known products having higher therapeutic efficacy show an high anti-secretory activity and are used, both in the acute and in the longterm (6 months and more) therapies. The drawback of these products is that they have a poor gastroprotective activity, when present. From a practical point of view this means that the gastric protection is not optimal and causes inconveniences especially in the long-term therapy. In this case the presence of frequent relapses due to the enfeeblement of gastric mucosa is noticed.
To overcome these inconveniences it is known in the art to add to said medicaments other anti-ulcer medicaments having a gastroprocective action: prostaglandins, bismuth salts (e.g. bismuth citrate) and antibiotics. In such way the removal of ulcerous pathology is achieved. However these combinations are not sastisfactory as to their tolerability in general. For example it is well known that prostglandins produce side effects (diarrhoea) towards the intestinal tract; bismuth salts frequently produce nausea and heart-burn. Antibiotics produce undesired gastrointestinal effects.
The need was felt to have available compositions active in the ulcer and gastric dyspesia treatment having improved therapeutic characteristic and tolerability, general and local, in particular having an improved gastroprotective activity combined with an high anti-secretion activity.
The Applicant has unexpectedly and surprisingly found pharmaceutical anti-ulcer compositions having an improved therapeutic activity and tolerability.
It is an object of the present invention pharmaceutical compositions comprising as essential components the following: component a): one or more components selected from the following classes:
wherein in the (A) class compounds
R=H, OCH
3
, OCEF
2
;
R
1
=H
3
, CH
3
;
R
2
=CH, CH
3
;
R
3
=CH
3
, CH
2
—CF
3
, (CH
2
)
3
—OCH
3
;
wherein in the (B) class compounds:
R
I
3
, R
I
4
equal to or different fromn each other, are respectively free valence, hydrogen, —N════C(NH
2
)
2
, —CH
2
—N(CH
3
)
2
;
Y=S, N—R
I
6
, CR
I
7
R
I
8
;
X=O, S, N—R
I
1
;
R
I
2
=H, CH
3
;
n=0, 1;
Z=N—CN, N—SO
2
NH
2
, CH—NO, or
R
I
5
=H, —NH—CH
3
, NH
2
;
R
I
6
, R
I
7
, R
I
8
, R
I
1
, equal to or different from each other, are hydrogen, free valence;
component b): one or more organic compounds containing the —ONO
2
function, or one or more inorganic compounds containing the —NO group, or mixtures thereof, said compounds being characterized in that they are NO nitric oxide donors, i.e. when they are brought into contact in vitro with cells of the vasal endothelium, platelets, etc., and after incubation of 5 minutes at a temperature of 37° C., are capable to release NO and to activate the cGMP synthesis (Guanosine cyclic 3′,5′-(hydrogen phosphate)), as shown by the used specific tests which will be described in detail further on.
The present invention compositions are obtainable by directly mixing the components a) and b).
The molar ratio between the components a) and b) can vary within wide limits, from 1:0.1 to 1:5, preferably from 1:0.5 to 1:2.
As regards the component a), the preferred (A) compounds are the following:
when R═OCH
3
, R
1
═CH)
3
, R
1
═CH
3
, R
3═CH
3
, Omeprazole residue;
as in Omeprazole, but with R═OCHF
2
, R
1
═OCH
3
, R
2
═H, Pantoprazole residue;
as in Omeprazole, but with R═H, R
2
═H, R
3
═(CH
2
)
3
—OCH
3
, Rabeprazole residue;
as in Rabeprazole, but with R
3
═CH
2
—CF
3
, Lansoprazole residue;
in component a) the preferred compounds of formula (B) are the following:
when in formula (B) X═N—R
I
1
with R
I
1
free valence, Y═N—R
I
6
with R
I
6
═H, R
I
3
═H, R
I
4
is free valence and forms with R
I
1
a double bond, R
I
2
═CH
3
, n=1, R
I
3
═—NH—CH
3
, Z═N—CN, Cimetidine residue;
when X═N—R
I
1
with R
I
1
free valence, Y═S,
R
I
3
═—N═C(NH
2
)
2
, R
I
4
is free valence and forms with R
I
1
a double bond, R
I
2
═H, n=1 R
I
5
═H, Z═(VII
A
), Ebrotidine residue;
as in Ebrotidine but with n=0, R
I
5
═NH
2
and Z═N—SO
2
NH
2
, Famotidine residue;
as in Ebrotidine but with R
I
3
═—CH
2
—N(CH
3
)
2
, R
I
5
═—NH—CH
3
and Z═CH—NO
2
, Nizatidine residue;
as in Nizatidine, but with X=oxygen, Y=CR
I
7
R
I
8
with R
I
7
hydrogen and R
I
8
free valence, R
I
4
is a free valence and forms with R
I
9
a double bond, Ranitidine residue.
In the preparation of the invention compositions also the isomers of one or more compounds of each component can be used.
The components belonging to (A) and (B) classes are prepared according to methods described in “The Merck Index 12
a
Ed.”(1996), herein incorporated by reference.
In the formula (A) compounds of component a) also the compounds having the following intramolecular ring are comprised, obtainable by treating the precursors in an acid aqueous medium (ref. A Textbook of Drug Design and Development, Harwood academic publisher, 1991, pag. 140):
wherein N
AI
and C
AII
are, respectively, the nitrogen and the carbon atom in 1 and 2 position of the pyridine ring of formula (A) and C
B2
and N
B3
the carbon and nitrogen atom, respectively, in 2 and 3 position of the imydazole ring (1 position of the imydazole ring is that of the proton nitrogen).
Instead of the formula (A) and (B) compounds of component a) the corresponding salts with organic or inorganic salts, obtainable by reactions known to the skilled in the art, can be used. examples of usable inorganic ions are the following: hydrochlorides, nitrates, suiphates, phosphates, etc.; among the organic ones maleates, oxalates, acetates, succinates, etc. can be mentioned. Compositions containing nitrates are preferred.
The salts with the preferred compounds of the component a) are those corresponding to the preferred compounds of formula (A) or (B).
In the compositions according to the present invention salts of the compound of the above formulas contain at least one anion mole/compound mole. Preferably the ratio between the anion and compound moles is unitary. Salts having a higher molar ratio are obtained when in the molecule other basic enough aminic groups to be salif ied are present.
For example the salts of the class (A) and (B) compound with nitric acid are prepared according to the following methods.
When the substance to be salified is available as free base or as a corresponding salt soluble in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is prepared by dissolving the substance in the solvent at a concentration preferably equal or higher than 10% w/v, by adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound. The nitric acid is preferably diluted in the same solvent. Preferably during and after the addition the mixture is cooled to temperatures in the range 20° C.-0° C. The product is generally recovered by filtration and washed with the solvent.
When on the contrary the substance is not very soluble, or it is available as a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents may be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. Precipitation can be quickened by diluting then the s
Arent Fox Kintner Plotkin & Kahn
Nicox S.A.
Weddington Kevin E.
LandOfFree
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